Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease

Abstract

SummaryAlzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions 1 . Memory decline in early stages of Alzheimer's is mostly limited to episodic memory, for which the hippocampus (HPC) plays a crucial role 2 . However, it has been uncertain whether the observed amnesia in early stages of Alzheimer's is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early Alzheimer's, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are utilized, revealing a retrieval, rather than a storage impairment. Prior to amyloid plaque deposition, the amnesia in these mice is age-dependent 3 -5 , which correlates with a progressive reduction of spine density of hippocampal dentate gyrus (DG) engram cells. We show that optogenetic induction of long-term potentiation (LTP) at perforant path (PP) synapses of DG engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of DG engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in early stages of Alzheimer's disease.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature

Inhibitory engrams in perception and memory

“…For instance, it conceptually distinguishes between behavioral amnesia arising from defects in storage and behavioral amnesia arising from defects in recall. It is therefore relevant to recent work showing that a memory engram remains preserved in amnesic mice that do not express contextual fear memory (66,67). Consistent with the framework we present here, in the mouse models of Alzheimer's disease, memory storage largely remains intact, In this illustration, these peaks constitute excitatory and inhibitory engrams, respectively.…”

Adenosine A 1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

“…On the other hand, the most common psychoactive drug in the world (caffeine), an adenosine receptor antagonist that boosts neuronal activity, protects against AD (39). Stimulation of the perforant path in an Aβ-based mouse model is sufficient to restore memory retrieval (40). Similarly, transcranial magnetic stimulation in humans increases brain network activity and performance of associative memory, emphasizing the benefit of increased bona fide network activity (41).…”

To master memory, researchers pursue its roots

“…But such studies in animals, by demonstrating the malleability of memory, could suggest novel therapeutic strategies. In a mouse model of earlystage Alzheimer's, Tonegawa's group showed that stimulating engram cells in the dentate gyrus can help animals access a memory that once seemed "lost" (11). His laboratory also reduced the effects of negative memories by stimulating neurons associated with a fear engram while introducing male mice to females (a positive experience), suggesting possible future directions for posttraumatic stress disorder and depression research (12).…”